Catalysts for ring-closing metathesis

ABSTRACT

A catalyst composition is provided, which may be used for ring closing metathesis. In the composition, a catalyst is immobilized on a siliceous mesocellular foam support. A suitable catalyst for use in the composition is a Grubbs-type catalyst or a Hoveyda-Grubbs-type catalyst.

This invention relates to a catalyst composition comprising a catalystand a support, which may be used in a ring-closing metathesis (RCM)reaction.

BACKGROUND

Ring-closing metathesis (RCM) is used for synthesizing cyclic compounds.

RCM has played a key role in the generation of cyclic motifs sinceGrubbs and co-workers reported the now well-defined ruthenium catalysts.(See, for example, Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R.H. Angew. Chem. Int. Ed. Engl. 1995, 34, 2039.) Grubbs catalysts andHoveyda-Grubbs catalysts have found wide application, including in thesynthesis of various heterocyclic and macrocyclic natural products, andother polymers. However, industry, including the pharmaceutical industryhas not yet widely adopted RCM in large-scale manufacturing. Reasons forthis include the high cost of the ruthenium-containing compounds, andthe relatively high metal leaching.

Attempts have been made to immobilize these homogeneous catalyticcomplexes on several types of supports. Many groups have reported on theimmobilization of the first- and second-generation Grubbs' catalysts(see, for example, Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett.2001, 3, 3225). Others have reported on the immobilization of reusablemodifications of these catalysts (see, for example, Kingsbury, J. S.;Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc.1999, 121, 791; and Gessler, S.; Randl, S.; Blechert, S. TetrahedronLett. 2000, 41, 9973). Immobilization techniques have been reportedusing: soluble polymers (see, for example, Yao, Q. Angew. Chem. Int. Ed.Engl. 2000, 39, 3896; and Yao, Q.; Motta, A. R. Tetrahedron Lett. 2004,45, 2447); insoluble polymers (see, for example, Barrett, A. G. M.;Camp, S. M.; Roberts, R. S. Org. Lett. 1999, 1, 1083; Nieczypor, P.;Buchowicz, W.; Meester, W. J. N.; Rutjes, F. P. J. T.; Mol, J. C.Tetrahedron Lett. 2001, 42, 7103; Akiyama, R.; Kobayashi, S. Angew.Chem. Int. Ed. Engl. 2002, 41, 2602; Grela, K.; Tryznowski, M.; Bieniek,M. Tetrahedron Lett. 2002, 43, 9055; and Halbach, T. S.; Mix, S.;Fischer, D.; Maechling, S.; Krause, J. O.; Sievers, C.; Blechert, S.;Nuyken, O.; Buchmeiser, M. R. J. Org. Chem. 2005, 70, 4687); monolithicgels (see, for example, Kingsbury, J. S.; Garber, S. B.; Giftos, J. M.;Gray, B. L.; Okamoto, M. M.; Farrer, R. A.; Fourkas, J. T.; Hoveyda, A.H. Angew. Chem. Int. Ed. Engl. 2001, 40, 4251); ionic liquids (see, forexample, Audic N.; Clavier, H.; Mauduit, M.; Guillemin, J.-C. J. Am.Chem. Soc. 2003, 125, 9248; and Yao, Q.; Zhang, Y. Angew. Chem. Int. Ed.Engl. 2003, 42, 3395); fluorous materials (see, for example, Yao, Q.;Zhang, Y. J. Am. Chem. Soc. 2004, 126, 74; and Matsugi, M.; Curran, D.P. J. Org. Chem. 2005, 70, 1636); and silica (see, for example, (Melis,K.; Vos, D. D.; Jacobs, P.; Verpoort, F. J. Mol. Catal. A: Chem. 2001,169, 47). However, immobilized catalysts obtained by these methodsgenerally also suffer from shortcomings, such as, low reactivity (e.g.,due to diffusion-related issues), reduced activity upon reuse,requirement for further purification, etc.

Ring-opening metathesis polymerization (ROMP) by (a) glass-type (see,for example, Kingsbury, J. S.; Garber, S. B.; Giftos, J. M.; Gray, B.L.; Okamoto, M. M.; Farrer, R. A.; Fourkas, J. T.; Hoveyda, A. H. Angew.Chem. Int. Ed. Engl. 2001, 40, 4251) and (b) one-pot functionalizedmonolith (see, for example, Sinner, F.; Buchmeiser, M. R. Macromolecules2000, 33, 5777; and Mayr, M.; Mayr, B.; Buchmeiser, M. R. Angew. Chem.Int. Ed. Engl. 2001, 40, 3839) have also been reported. Both seem to becomplicated procedures, despite the apparent advantages of applicationto library generation and ability to be recycled.

A silica gel-supported metathesis catalyst has also been reported, withreported mild reaction conditions, high turnover number and ease ofpurification. (See Fischer, D.; Blechert, S. Adv. Synth. Catal. 2005,347, 1329.) However, this catalyst does not recycle well, even forreaction involving a simple substrate. Only 68% yield was reportedachieved in three runs.

Others have reported on the use of mesoporous compositions as supportsfor catalysts. (See, for example, U.S. Pat. No. 6,544,923 and XiaohuaHuang, Chem. Comm., 2007, DOI:10.1039/b615564).

Siliceous mesocellular foams (MCF) have been prepared having athree-dimensional, interconnected pore structure with ultralargecell-like pores (e.g., 24-42 nm) that are connected by windows of, forexample, 9-22 nm. (See, for example, Schmidt-Winkel, P.; Lukens, W. W.,Jr.; Zhao, D.; Yang, P.; Chmelka, B. F.; Stucky, G. D. J. Am. Chem. Soc.1999, 121, 254; Schmidt-Winkel, P.; Lukens, W. W., Jr., Yang, P.;Margolese, D. I.; Lettow, J. S.; Ying, J. Y.; Stucky, G. D. Chem. Mater.2000, 12, 686; Lettow, J. S.; Han, Y. J.; Schmidt-Winkel, P.; Yang, P.;Zhao, D.; Stucky, G. D.; Ying, J. Y. Langmuir 2000, 16, 8291; Lettow, J.S.; Lancaster, T. M.; Glinka, C. J.; Ying, J. Y. Langmuir 2005, 21,5738; and Yu, H.; Ying, J. Y. Angew. Chem. Int. Ed. 2005, 44, 288.)

In general, known procedures have not generated sufficiently efficientheterogenized catalysts for industrial applications. These immobilizedcatalysts have generally been difficult to prepare with high cost, poorenvironmental compatibility, and relatively poor catalytic activity.

SUMMARY

According to one broad aspect of the present invention, there isprovided a catalyst composition comprising a ruthenium catalystimmobilized on a siliceous mesocellular foam support. In one embodiment,the ruthenium catalyst is a Grubbs catalyst or a Hoveyda-Grubbscatalyst.

According to another embodiment of the present invention, there isprovided a catalyst composition comprising a catalyst:

immobilized on a siliceous mesocellular foam support. The catalystcomposition may be immobilized on the siliceous mesocellular foamsupport using a linking group comprising a carbamate or silyl group, forexample. In an exemplary embodiment, the carbamate or silyl group isattached to the siliceous mesocellular foam support through an alkylspacer, such as, for example, a C₁-C₆ alkyl group. In a furtherexemplary embodiment, the carbamate is a methyl carbamate, and the silylgroup is substituted by one or two methyl groups. In a still furtherexemplary embodiments, the linking group is —X—C(O)N(H)CH₂CH₂CH₂—,wherein X is CH₂O or O, or the linking group is—Si(CH₃)₂—[(C₁-C₆)alkyl]_(n)-, wherein n is 0, 1, 2, 3, 4, 5, or 6. In ayet further exemplary embodiment, the linking group is attached to the2-position of the catalyst:

In another exemplary embodiment of the present invention, the siliceousmesocellular foam support comprises trimethylsilyl. In a furtherembodiment, the siliceous mesocellular foam support comprises spherical,monodisperse siliceous mesocellular foam microparticles. The siliceousmesocellular foam support may have an average pore diameter of about 24to about 42 nm.

The catalyst composition according to the present invention may be usedin a ring-closing metathesis reaction. In another invention embodiment,the catalyst composition is recycled for use in a further ring-closingmetathesis reaction.

In a further broad aspect, the present invention provides a method forpreparing a catalyst composition comprising immobilizing a Grubbscatalyst or a Hoveyda-Grubbs catalyst on a siliceous mesocellular foamsupport. In an exemplary embodiment, the catalyst is:

DETAILED DESCRIPTION

In the catalyst compositions of the invention, a catalyst is immobilizedon a solid support comprising siliceous mesocellular foams (MCF). In oneexemplary embodiment, spherical, monodisperse MCF is used as support forRCM catalysts including in, for example, batch reactor and packed bedreactor applications. In one embodiment, the pores have an averagediameter of about 24 to about 42 nm, and may have open “windows” betweenthe pores of about 9 to about 22 nm. Spherical MCF microparticles can bemodified easily in terms of microstructure, pore size and surfacechemistry for specific applications, as will be apparent to a personskilled in the art. The physical and chemical properties of MCF allowthis material to be easily handled both at the laboratory andmanufacturing scales.

The heterogenized catalysts of the present invention may be used forring-closing metathesis (RCM). The catalyst compositions obtainedaccording to the present invention may be beneficial to the chemical andpharmaceutical industries, such as, for example, in the large-scaleproduction of drug candidates and food products, and the large-scalesynthesis of fine and specialty chemicals. The catalyst compositions ofthe invention may be used on a wide variety of substrates under mildreaction conditions, including for ring closure of diene containingstarting materials.

The catalyst immobilized on the MCF is not particularly limited. For RCMreactions, a ruthenium containing catalyst, such as a Grubbs typecatalyst or a Hoveyda-Grubbs type catalyst, may be used. Hoveyda-Grubbscatalysts have the following general structure:

wherein: P is platinum, Cy is cyclohexyl; and Mes is mesityl. Suitablederivatives of these catalysts are also within the contemplation of thepresent invention.

Ruthenium ligands may be immobilized on the support using a suitablelinking group, including, without limitation, a Hoveyda-type ligand.

Non-limiting examples of other catalysts and linking groups aredescribed in more detail herein.

The catalyst compositions of the invention were observed to exhibitactivity and reusability suitable for RCM of various types ofsubstrates.

In one exemplary embodiment of the present invention, immobilizedsecond-generation Hoveyda-Grubbs catalysts using MCF as a solid supportwere obtained. Isopropoxystyrene ligands were fixed on the solid surfaceof the MCF support. The immobilization of catalysts 4a and 4b isillustrated in Scheme 1.

Reaction Conditions Scheme 1:

-   (a) 1.05 equiv. 3-isocyanopropyltriethoxysilane, 0.01 equiv.    4-dimethylaminopyridine, 3 equiv. triethylamine, dichloromethane    (DCM), 45° C., 93-95%.-   (b) Partially trimethylsilyl (TMS)-capped MCF, toluene, 100° C.;    hexamethyldisilazane (HMDS), 80° C., 95-99%.-   (c) 1.05 equiv. second-generation Grubbs' catalyst, 1.05 equiv.    CuCl, DCM, 50° C., 90-94%.

In Scheme 1, starting with commercially available3-bromo-4-hydroxybenzaldehyde and 2,5-dihydroxybenzaldehyde, the alcohol2a and phenol 2b were readily prepared using known procedures.Intermediates 2a and 2b were immediately reacted with3-isocyanylpropyltriethoxysilane to generate the correspondingcarbamates, which were immobilized onto the surface of the partiallytrimethylsilyl-capped (TMS-capped) MCF by heating at 100° C. in toluene.In order to minimize the interference from MCF's residual surfacesilanols, the catalyst was post-capped by treatment withhexamethyldisilazane (HMDS) to obtain the isopropoxystyrene ligands 3aand 3b.

In another invention embodiment, heteroatom-free alkyl chains of tunablelength were introduced to suppress the possibility of undesirableinterference with the linker group in the catalytic reactions (Scheme2).

Reaction Conditions Scheme 2:

-   (a) (i) 1.05 equiv. Mg, 0.01 equiv. 12, tetrahydrofuran (THF),    reflux, (ii) 3 equiv. Me₂SiCl₂ for 3c, ClSiMe₂(CH)₂Cl for 3d,    ClSiMe₂(CH)₆Cl for 3e, 90-96%.-   (b) Partially TMS-capped MCF, 3 equiv. triethylamine, toluene, room    temperature; HMDS, 80° C., 99%.-   (c) 1.05 equiv. second-generation Grubbs' catalyst, 1.05 equiv.    CuCl, DCM, 50° C., 90-94%.

The 2-isopropoxy-4-bromostyrene 2c was readily silylated via Grignardreaction using three types of dichlorides, which were immobilized ontothe surface of MCF by heating in toluene in the presence oftriethylamine to derive the immobilized ligands 3c-3e in excellentyields.

The immobilized catalyst 4a-4-e of Schemes 1 and 2 were isolated byrefluxing the catalyst and the functionalized MCF 3a-3e in refluxingdichloromethane (DCM) in the presence of copper(I) chloride, followed byfiltration and drying. Catalysts 4a-4-e were prepared with differentligand and metal loadings, and stored for more than several monthswithout losing any activity.

The immobilized catalysts 4a-4-e were tested for RCM in dichloromethane(DCM), toluene or tetrahydrofuran (THF) by using diethyl diallylmalonate5a and monitoring its conversion to the cyclized product 5b.

RCM was determined as a percent (%) conversion (Conv) of diene 5a toproduct 5b over a time (t). The results are shown in Table 1. Unlessotherwise noted, all reactions were performed over 5 mol % of catalyst(Cat) at 0.05 M in solvent at room temperature. The TMS/Ligand/RuLoadings in mmol/g were determined by elemental analysis. The percentconversion was determined by gas chromatography (GC).

TABLE 1 TMS/Ligand/Ru Conversion (%) Loadings t = 0.5 t = 1 t = 1.5 t =2 Cat (mmol/g) Solvent hour hour hours hours 1 4a 0.6/0.36/0.14 DCM 99100 Toluene 90 98 THF 21 63 2 4a 0.6/0.29/0.08 DCM 64 91 98 100 Toluene88 97 100 THF 9 27 56 78 3 4a 0.6/0.36/0.26 DCM 60 91 100 Toluene 63 7276 78 4 4a 0.6/0.36/0.26 DCM^(a) 89 100 Toluene^(a) 94 97 5 4a0.6/0.36/0.26 DCM^(b) 31 58 75 86 Toluene^(b) 43 51 55 59 THF^(b) 2 6 1918 6 4a 0.8/0.22/0.18 DCM^(a) 89 100 Toluene^(a) 96 100 7 4a  0/1.10/0.18 DCM 26 44 56 63 8 4a   0/1.10/0.18 DCM^(a) 58 85 99 9 4b  0/0.72/0.22 DCM 13 24 33 40 Toluene 26 37 43 48 THF 16 33 47 58 10 4b0.4/0.44/0.16 DCM 81 97 100 11 4b 0.4/0.44/0.16 DCM^(a) 89 100Toluene^(a) 94 97 12 4c 0.8/0.35/0.21 DCM 16 23 27 30 13 4d0.8/0.27/0.25 DCM 39 69 87 96 14 4e 0.8/0.28/0.24 DCM 48 78 92 97 15 7 —DCM 95 100 Toluene 85 94 97 99 16 1b — DCM 98 100 Toluene 99 100 THF 8798 99 100 ^(a)Performed at 0.1 M in solvent. ^(b)Performed over 2.5 mol% of catalyst.

It was observed that the reaction rate was dependent on the solventused. It was observed that DCM and toluene were more effective than THFfor all catalyst systems tested. The loadings of ligand and rutheniumdid not seem to considerably affect the catalytic activity. However, itis noteworthy that the catalysts with very high ligand loadings andpartially (<30%) loaded ruthenium showed reduced reaction rates (Entries7-9). Without being bound by any theory, the high abundance of freeligands might have provided the reactive ruthenium carbene species moreopportunities to return to the solid phase, which in turn slowed downthe reaction. It was observed that the reaction became faster at ahigher concentration (0.1 M) (Entries 4, 6, 8, and 11), without formingany significant amount of side-products as detected by nuclear magneticresonance (NMR) spectroscopy. When a lower amount of 4a (2.5 mol %) wasused, the reaction rate was decreased significantly (Entry 5).

It was observed that the reaction was accelerated with the increasedflexibility of the linker group composed of non-coordinating hydrocarbonalkyl chain (Entries 12-14). Without being bound by any theory, when ashort or rigid linker is used, the increased interaction between thecatalytic center and the MCF surface may be interfering with andretarding the release and return of the ruthenium during the reaction.

To examine the role of the carbamate group in the linker, homogeneouscatalyst 7 was prepared in good yield from alcohol 2a and n-butylisocyanate in the same manner as 4a via intermediate 6 (Scheme 3).

Reaction Conditions for Scheme 3:

-   (a) 1.05 equiv. n-butyl isocyanate, 0.01 equiv. 4-DMAP, 3 equiv.    triethylamine, DCM, 45° C., 95%.-   (b) 1.05 equiv. second-generation Grubbs' catalyst, 1.05 equiv.    CuCl, DCM, 50° C.; column chromatography; recrystallization, 85%.

It was observed that the carbamate moiety did not notably affect thecatalytic activity, and the reaction rate of 7 was comparable to thecommercially available second-generation Hoveyda-Grubbs' catalyst 1b(Entries 15 and 16 in Table 1).

The recyclability of immobilized catalysts 4a-4-e (Cat) in thering-closing metathesis reaction of diene 5a to product 5b in DCM wasevaluated over a time (t) of 1-2 hours (h). The results are shown inTable 2. Unless otherwise noted, all reactions were performed over 5 mol% catalyst at 0.05 M in DCM at room temperature. The percent (%)conversion was determined by gas chromatography (GC).

TABLE 2 Loading Cat (mmol/g) t Run# 1 2 3 4 5 6 7 8 9 10 1 4a 0.36/0.141 h Conv >99 >99 97 98 95 93 91 91 83 80 2 4a 0.36/0.26 1 h^(a) (%) >9998 98 92 91 90 91 78 80 77 3 4a 0.36/0.26 0.5 h^(b) >99 99 98 97 97 9494 87 92 93 4 4a 0.22/0.18 2 h 99 99 97 96 94 97 85 82 79 79 5 4b0.44/0.16 2 h 98 93 98 97 90 97 85 77 77 76 ^(a)Performed at 0.1 M inDCM. ^(b)Performed under reflux.

Excellent conversions were observed (Table 2) for up to 6 runs (90-97%),followed by gradual loss of activity in subsequent runs. A decrease inactivity to 76-80% conversions was noted for run #10 at roomtemperature. Without being bound by any theory, this loss in activitycould be due to deactivation and/or leaching of the ruthenium carbenespecies, which should be in the solution phase during catalyticreactions. It was noteworthy that the recyclability was improved at anelevated temperature (Entry 3 in Table 2). Without being bound by anytheory, the shorter reaction time might have reduced catalystdeactivation, and the elevated temperature might have facilitated theethylene removal.

Ability to recycle was also examined with toluene as solvent. Theresults are shown in Table 3. Unless otherwise noted, all reactions wereperformed over 5 mol % of immobilized catalyst 4a or 4b (Cat) at 0.05 Min toluene at room temperature for a time (t) of 1-2 hours (h). Thepercent (%) conversion (Conv) was determined by gas chromatography (GC).

TABLE 3 Loading Cat (mmol/g) t Run# 1 2 3 4 5 6 7 8 9 10 1 4a 0.36/0.141.5 h Conv >99 96 88 86 92 85 88 88 87 86 2 4a 0.29/0.08 1.5 h (%) >9988 87 75 80 81 82 85 77 78 3 4a 0.22/0.18 2 h 99 89 80 85 85 81 86 75 7977 4 4b 0.44/0.16 2 h 95 90 78 87 87 77 87 76 81 79

When toluene was used as the solvent, substantial loss in activity wasnoted after the first recycle (Table 3). However, subsequent loss inactivity was more gradual so that 77-86% conversions were achieved forrun #10 at room temperature.

The performance of the MCF-supported catalysts 4, was examined for theRCM of other dienes (see Table 4). The reaction time was determined inthe first run for a near-complete conversion of the specific substrate,and was kept constant for the subsequent runs to monitor any decrease incatalytic activity. Unless otherwise noted, all reactions were performedover 5 mol % of 4a at 0.05 M in DCM for 1.5 hours at room temperature.All percent (%) conversions were determined by gas chromatography (GC)except for entry 9; the percent conversions for entry 9 were determinedby ¹H-NMR spectroscopy (400 MHz).

TABLE 4 Substrate Product Run Conversion (%) 1

1 2 3 4 5 6 7 8 >99 (97)^(a) 98 97 96 92 89 84 >99^(b) 2

1 2 3 4 5 6 7 94 (93)^(a) 93 93 93 91 92 91 3

1 2 3 4 5 6 7 94 92 91 90 88 87 86 4

1 2 3 4 5 6 7 96 (92)^(a) 93 91 85 76 67 53 5

1 2 3 4 5 6 7 8 >99 (97)^(a) >99   98 95 86 86 55   95^(c) 6

1 2 3 4 5 84 54 23  6  2 7

1 2 3 4 5 >99 (97)^(a) 100  99 98 98 8

1 60 (40)^(f) 9

1 2 3 4 5 88 75 71 58 34 ^(a)Isolated yield by column chromatography onsilica gel. ^(b)Performed for 6 h. ^(c)Performed for 4.5 h.^(d)Performed for 1 h. ^(e)Performed for 2 h. ^(f)yield for themonocyclic compound.

It was observed that RCM of the nitrogen-containing diene 8a producedthe five-membered ring 8b in good yield for consecutive runs (Entry 1,Table 4), with comparable reaction rate as in the RCM of 5a. Althoughthe recyclability was observed to drop after five runs, it was observedthat the full conversion could be obtained by increasing the reactiontime. Formation of the seven-membered ring containing heteroatom wasalso observed to be efficient, despite gradual loss in activity in sevenconsecutive runs (Entries 2 and 3, Table 4). Reaction of hindered diene11a was observed to proceed more slowly, and the activity loss wasobserved to be more significant over consecutive runs with an increasedreaction time per cycle (Entry 4, Table 4). The reaction efficiencyappeared similar in the case of an internal olefin, but therecyclability was observed to be lower than in the case of the terminalolefin in Entry 1. Without being bound by any theory, it is believedthat this is because the product inhibition became greater due to theincreased solubility of propene evolved in DCM (Entry 5, Table 4).Catalyst 4a showed significant loss in activity over consecutive runsfor RCM of substrate containing free alcohol (Entry 6, Table 4). Withoutbeing bound by any theory, this could be attributed to leachingproblems, or it might be due to stronger interactions between hydroxylgroups and the reactive catalytic species.

High catalyst recyclability was demonstrated for aliphatic ether 14a(Entry 7, Table 4), which are generally known to cause more seriousmetal leaching due to the coordinating ability of the oxygen toruthenium. It appeared that the catalyst system of the invention wasparticularly efficient for the aliphatic ether substrates, achieving≧98% conversion in 1 hour for all 5 runs. The enyne 15a produced amonocyclic compound, as well as the desired bicyclic analog (Entry 8,Table 4). This lack of selectivity is consistent with other findingsthat the formation of the six-membered monocyclic compound wasunavoidable in the catalysis by the second-generation Grubbs' catalyst.(See, for example, Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk,V.; Dolgonos, G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318.)Macrocycle was also successfully formed over 4a, although theconversions decreased over consecutive runs (Entry 9, Table 4).

Without being bound by any particular theory, it is believed that thecatalyst system is recycled by the return of the reactive catalyticspecies to the MCF-supported isopropoxystyrene ligand. To study the roleof the reactive catalytic species over multiple runs, excess free ligandwas used in a RCM of diene 5a in immobilized catalyst 4a. The results ofexperiments are presented in Table 5.

TABLE 5 Ligand/Ru Loading in 4a (mmol/g) t Run# 1 2 3 4 5 6 7 8 9 10 10.22/0.18 2 h Conv 98 99 98 98 97 97 91 90 90 85 2 1.10/0.18 2 h (%) 9996 99 99 98 97 94 93 92 91

For both Entries 1 and 2 in Table 5, reactions were performed over 5 mol% of 4a at 0.1 M in DCM at room temperature for a time (t) of 2 hours(h). For Entry 1, 5 mol % of MCF-supported free ligands 3a (0.22 mmolligand/g) was also added. For Entry 2, a high ligand loading and apartial Ru loading was used. The percent (%) conversion (Conv) wasdetermined by Gas Chromatography (GC).

The catalyst was observed to recycle over 10 runs in both cases in Table5, with better observed results in Entry 2. Although the reaction wasretarded with the introduction of excess free ligands, this approachsuccessfully improved catalyst recyclability. To compensate for theslower reaction rate, a higher concentration (0.1 M) was employed.

It was also observed that the presence of excess free ligands reducedruthenium leaching problems over multiple cycles. In Table 6, theactivity and leaching of catalyst 4a in the RCM of diene 14a wasstudied. Reactions for Entries 1 to 4 were performed over 5 mol % of 4a(0.36 mmol ligand/g, 0.26 mmol Ru/g) at 0.05 M in DCM. For Entries 2 and4, ligand 3a (0.22 mmol ligand/g) was added in the specified mol %. Thereaction was performed at the noted temperature (T) of either roomtemperature (r.t.) or reflux temperature. The time (t) was measured inhours (h). Ruthenium (Ru) residue in parts per million (ppm) wasdetermined by inductively coupled plasma-mass spectrometry (ICP-MS), andthe percent (%) conversion (Conv) was determined by gas chromatography.

TABLE 6 Ligand T t Run # 1 2 3 1 — r.t. 1 h Ru residue 35 [>99] 30 [99]20 [98] 2 5 mol % r.t. 2 h (ppm) 23 [99] 18 [99] 15 [98] 3 — reflux 0.5h [Conv. (%)] 13 [>99] 9 [>99] 7 [99] 4 5 mol % reflux 1 h 10 [99] 9[99] 9 [99]

Table 6 illustrates that when 5 mol % MCF-supported free ligands 3a wasadded to the RCM of 14a, the ruthenium concentration in the supernatantmeasured by ICP-MS at the end of each run was decreased, despite thelonger reaction time. The suppression of ruthenium leaching was observedto be particularly significant for reaction runs at room temperature.

The results in Table 6 support the earlier observation that the abilityto recycle can be enhanced by using excess free ligands and elevatedreaction temperatures.

EXPERIMENTAL PROCEDURE Tables 1-6

In general, catalyst activity as a function of percent conversion ineach of Tables 1 to 6 was determined by running the reactions in a vialcontaining a magnetic stir bar under argon at room temperature. The vialwas charged with catalyst (e.g., 4a-4-e in an amount of 5 μmol) andsolvent (e.g., DCM). The substrate (e.g., 5a, 8a-16a in an amount of 0.1mmol) was then injected. Conversions were monitored (e.g., by GC) afterfiltration through a short pad of silica gel by elution with solvent(e.g., DCM). In general, the reaction volume was 1-4 ml. For thoseexperiments where the ability of the catalyst system to recycle wasstudied, these reactions were generally run in a similar manner to thosefor studying catalyst activity. For the recycle studies, on completionof each run, the reaction vial was centrifuged at 4000 rpm for 3minutes, and the supernatant was characterized by flash columnchromatography and GC for isolated yield and conversion, respectively.The vial was charged with another aliquot of solvent (e.g., DCM),stirred for 1 minute, and centrifuged again. One more rinse wasperformed before the next run was conducted with fresh substrate.

Example 1 Preparation of Ligands 3a and 3b Step (a):

A Schlenk flask was charged with the corresponding alcohol 2a or 2b(10.0 mmol), 3-isocyanylpropyl-1-triethoxysilane (10.0 mmol),4-dimethylpyridine (0.10 mmol), triethylamine (20.0 mmol), and dried DCM(10 ml) under argon. The reaction mixture was heated for 48 hours underreflux. DCM and triethylamine were removed under reduced pressure.Hexane (10 ml) was added, and the precipitate was removed by filtration.The filtrate was concentrated under reduced pressure, and dried undervacuum to give the corresponding carbamate as a colorless oil, which wasused without further purification.

The general procedure of Step (a) using 2a (8.35 mmol) gave 3.63 g ofthe corresponding triethoxysilane: ¹H-NMR (400 MHz, CDCl₃): δ 0.64 (t,2H, J=8.0 Hz), 1.24 (t, 9H, J=7.2 Hz), 1.35 (d, 6H, J=6.0 Hz), 1.62 (m,2H), 3.19 (m, 2H), 3.82 (q, 6H, J=7.2 Hz), 4.54 (septet, 1H, J=6.0 Hz),5.03 (bs, 2H), 5.25 (dd, 1H, J=11.2, 1.4 Hz), 5.75 (dd, 1H, J=17.6, 1.4Hz), 6.86 (d, 1H, J=8.4 Hz), 7.04 (dd, 1H, J=17.6, 11.2 Hz), 7.22 (dd,1H, J=8.4, 2.2 Hz), 7.48 (d, 1H, J=2.2 Hz). ¹³C-NMR (100 MHz, CDCl₃): δ7.6, 18.3, 22.1, 23.3, 43.4, 58.4, 66.4, 70.9, 106.6, 114.0, 114.3,126.9, 128.6, 129.0, 131.7, 155.1, 156.5. MS (FAB): m/z (%) 438 (38)[M⁺−H], 392 (20) [M⁺−EtOH−H], 364 (16), 297 (5), 264 (18), 220 (89), 174(100). HRMS (FAB) calculated for C₂₂H₃₆NO₆Si: 438.2331, found 438.2328.

The general procedure of Step (a) using 2b (4.22 mmol) gave 1.77 g ofthe corresponding triethoxysilane: ¹H-NMR (400 MHz, CDCl₃): δ 0.68 (t,2H, J=8.0 Hz), 1.24 (t, 9H, J=7.2 Hz), 1.33 (d, 6H, J=6.0 Hz), 1.70(quintet, 2H, J=8.0 Hz), 3.26 (q, 2H, J=8.0 Hz), 3.83 (q, 6H, J=7.2 Hz),4.46 (septet, 1H, J=6.0 Hz), 5.24 (dd, 1H, J=11.2, 1.4 Hz), 5.42 (bs,2H), 5.69 (dd, 1H, J=17.6, 1.4 Hz), 6.84 (d, 1H, J=8.8 Hz), 6.96 (dd,1H, J=8.8, 2.2 Hz), 7.02 (dd, 1H, J=17.6, 11.2 Hz), 7.22 (d, 1H, J=2.2Hz). ¹³C-NMR (100 MHz, CDCl₃): δ 7.4, 18.7, 22.0, 22.9, 43.3, 58.3,71.3, 114.3, 114.9, 119.0, 121.4, 128.5, 131.1, 144.4, 152.2, 154.8. MS(FAB): m/z (%) 426 (37) [M⁺+H], 380 (100) [M⁺−EtOH+H], 178 (69). HRMS(FAB) calculated for C₂₁H₃₆NO₆Si: 426.2306, found 426.2299.

Step (b):

A Schlenk flask was charged with MCF (2.05 g, 0.60 mmol TMS/g) andplaced under vacuum for 24 hours at 120° C. The flask was purged withargon at room temperature, and charged with dried toluene (20 ml) andthe corresponding triethoxysilane (0.85 mmol) obtained from Step (a).The resulting mixture was heated for 48 hours at 100° C. Upon cooling toroom temperature, the solid was thoroughly rinsed with toluene, DCM,methanol, and DCM (50 ml each). The white solid obtained was transferredto a Schlenk flask, and dried under vacuum for 12 hours at 80° C. Aftercooling down to room temperature, the flask was placed in liquidnitrogen bath for 10 minutes, and HMDS (1 ml) was added under vacuum.The flask was sealed and then kept at 80° C. for 5 hours. The resultingsolid was cooled to room temperature, washed thoroughly with DCM (100ml), and then dried under vacuum for 24 hours to give the correspondingimmobilized ligand as a white powder.

Following this general procedure, intermediates 3a and 3b may beobtained:

Starting Material Elemental (amount) Intermediate (amount) Analysis 2a(0.42 mmol) 3a (1.00 g) C: 10.77 Used for preparation of 4a, H: 1.91Entries 1 and 3-5 of Table 1) N: 0.51 2a (0.85 mmol) 3a (2.18 g) C: 8.77Used for preparation of 4a, Entry H: 1.54 2 of Table 1 N: 0.40 2a (0.45mmol) 3a (2.00 g) C: 8.16 Used for preparation of 4a, Entry H: 1.66 6 ofTable 1 N: 0.31 2a (2.20 mmol) 3a (2.00 g) C: 14.15 Used for preparationof 4a, H: 2.02 Entries 7 and 8 of Table 1 N: 1.53 2b (1.11 mmol) 3b(1.32 g) C: 12.65 Used for preparation of 4b, Entry H: 1.88 9 of Table 1N: 1.01 2b (0.60 mmol) 3b (1.34 g) C: 9.77 Used for preparation of 4b,H: 1.72 Entries 10 and 11 of Table 1 N: 0.62

Example 2 Preparation of Ligands 3c-3e Step (a):

A two-necked flask equipped with a reflux condenser was charged withmagnesium (21.0 mmol), iodine (trace), and dried THF (50 ml), and heatedunder reflux. 4-Bromo-2-isopropoxystyrene (20.0 mmol) in THF (50 ml) wasadded slowly, and the resulting mixture was stirred under reflux untilmagnesium disappeared. After cooling to room temperature, the turbidsolution was added to a stirred solution of the corresponding dichloride(60.0 mmol) in THF (50 ml) at 0° C. The resulting solution was stirredfor 18 hours at room temperature. It was concentrated under reducedpressure, and hexane (20 ml) was added slowly under stirring. Theinsoluble substance was filtered off, and the filtrate was concentratedand dried under vacuum for 24 hours to give the correspondingchlorosilane as an oil, which was used without further purification.

The general procedure of Step (a) using dichlorodimethylsilane (20.0mmol) gave 5.05 g of the corresponding chlorosilane 3c: ¹H-NMR (400 MHz,CDCl₃): δ 0.68 (s, 6H), 1.36 (d, 6H, J=6.0 Hz), 4.59 (septet, 1H, J=6.0Hz), 5.27 (dd, 1H, J=11.2, 1.4 Hz), 5.78 (dd, 1H, J=17.6, 1.4 Hz), 6.91(d, 1H, J=8.4 Hz), 7.05 (dd, 1H, J=17.6, 11.2 Hz), 7.46 (dd, 1H, J=8.4,1.6 Hz), 7.69 (d, 1H, J=1.6 Hz). ¹³C-NMR (100 MHz, CDCl₃): δ 2.2, 22.0,70.3, 113.0, 114.5, 126.6, 127.2, 131.7, 131.8, 133.8, 156.9.

The general procedure of Step (a) using 1,2-bis(dichlorosilyl)ethane(15.0 mmol) gave 5.01 g of the corresponding chlorosilane 3d: ¹H-NMR(400 MHz, CDCl₃): δ 0.30 (s, 6H), 0.42 (s, 6H), 0.76 (s, 4H), 1.39 (d,6H, J=6.0 Hz), 4.61 (septet, 1H, J=6.0 Hz), 5.28 (dd, 1H, J=11.2, 1.4Hz), 5.79 (dd, 1H, J=17.6, 1.4 Hz), 6.91 (d, 1H, U=8.4 Hz), 7.10 (dd,1H, J=17.6, 11.2 Hz), 7.37 (dd, 1H, J=8.4, 1.6 Hz), 7.61 (d, 1H, J=1.6Hz). ¹³C-NMR (100 MHz, CDCl₃): δ −3.4, 1.0, 7.3, 11.5, 22.2, 70.3,113.0, 114.1, 127.0, 129.1, 132.2, 132.3, 134.3, 156.1.

The general procedure of Step (a) using 1,6-bis(dichlorosilyl)hexane(20.0 mmol) gave 7.78 g of the corresponding chlorosilane 3e: ¹H-NMR(400 MHz, CDCl₃): δ 0.24 (s, 6H), 0.40 (s, 6H), 0.70-0.85 (m, 4H), 1.32(bs, 8H), 1.37 (d, 6H, J=6.0 Hz), 4.57 (septet, 1H, J=6.0 Hz), 5.24 (dd,1H, J=11.2, 1.4 Hz), 5.76 (dd, 1H, J=17.6, 1.4 Hz), 6.88 (d, 1H, J=8.4Hz), 7.07 (dd, 1H, J=17.6, 11.2 Hz), 7.34 (dd, 1H, J=8.4, 1.6 Hz), 7.59(d, 1H, J=1.6 Hz). ¹³C-NMR (100 MHz, CDCl₃): δ−2.6, 1.9, 16.1, 19.2,22.4, 23.1, 24.0, 32.8, 33.4, 70.5, 113.2, 114.1, 127.1, 130.3, 132.3,132.5, 134.4, 156.1.

Step (b):

A Schlenk flask was charged with MCF (3.00 g, 0.80 mmol TMS/g), andplaced under vacuum for 24 hours at 120° C. The flask was purged withargon at room temperature, and charged with triethylamine (0.44 ml),dried toluene (40 ml), and the corresponding chlorosilane (1.05 mmol).The resulting mixture was stirred for 24 hours at room temperature. Thewhite solid was thoroughly rinsed by toluene, DCM, methanol, and DCM (50ml each), which was transferred to a Schlenk flask and dried undervacuum for 12 hours at 80° C. After cooling down to room temperature,the flask was placed in liquid nitrogen bath for 10 min, and HMDS (1 ml)was added under vacuum. The flask was sealed and then kept at 80° C. for5 hours. The resulting solid was cooled to room temperature, washedthoroughly with DCM (100 ml), and then dried under vacuum for 24 hoursto give the corresponding immobilized ligand as a white powder.

Following this general procedure, intermediates 3c, 3d and 3e may beobtained:

Amount corresponding Elemental precursor Intermediate (amount) Analysis1.05 mmol 3c (3.23 g) C: 8.16 Used for preparation of 4c, H: 1.39 Entry12 of Table 1 N: <0.07 0.70 mmol 3d (2.20 g) C: 9.96 Used forpreparation of 4d, H: 2.04 Entry 13 of Table 1 N: <0.06 1.05 mmol 3e(3.46 g) C: 10.91 Used for preparation of 4e, H: 2.07 Entry 14 of Table1 N: <0.03

Example 3 Preparation of Catalysts 4a-4-e

A two-necked flask equipped with a reflux condenser was charged withligand 3a (500 mg, 0.36 mmol/g), second-generation Grubbs' catalyst(0.18 mmol), copper chloride (0.18 mmol), and dried DCM (10 ml) underargon. The reaction mixture was heated for 18 hours under reflux instream of argon. The reaction mixture gradually changed from dark brownto deep green. After cooling to room temperature, the fine powder waswashed thoroughly with DCM (100 ml) under open atmosphere, and driedunder vacuum for 24 h to give the immobilized catalyst 4a (578 mg) as agreen powder.

The skilled person will readily appreciate how this general proceduremay be adapted to obtain catalysts 4b-4-e.

Using this general procedure, catalysts 4a-4-e may be obtained:

Intermediate Catalyst (amount) (amount) Elemental Analysis 3a (500 mg)4a (536 mg) Entry 1, Table 1 3a (1.00 g) 4a (1.04 g) Entry 2, Table 1 3a(500 mg) 4a (578 mg) C: 15.30 Entries 3-5 of Table 1 H: 2.26 N: 1.07 3a(1.00 g) 4a (1.09 g) Entry 6 of Table 1 3a (500 mg) 4a (546 mg) C: 17.26Entries 7-8 of Table 1 H: 2.31 N: 1.30 3b (250 mg) 4b (279 mg) Entry 9of Table 1 3b (500 mg) 4b (541 mg) Entries 10-11 of Table 1 3c (500 mg)4c (566 mg) C: 12.99 Entry 12 of Table 1 H: 1.97 N: 0.59 3d (2.00 g) 4d(2.27 g) C: 14.02 Entry 13 of Table 1 H: 2.32 N: 0.69 3e (2.00 g) 4e(2.25 g) C: 14.89 Entry 14 of Table 1 H: 2.43 N: 0.67

Although the foregoing invention has been described in some detail byway of illustration and example, and with regard to one or moreembodiments, for purposes of clarity of understanding, it is readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes, variations and modifications maybe made thereto without departing from the spirit or scope of theinvention as described in the appended claims.

It must be noted that as used in the specification and the appendedclaims, the singular forms of “a”, “an” and “the” include pluralreference unless the context clearly indicates otherwise.

Unless defined otherwise all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this invention belongs.

All publications, patents and patent applications cited in thisspecification are incorporated herein by reference as if each individualpublication, patent or patent application were specifically andindividually indicated to be incorporated by reference. The citation ofany publication, patent or patent application in this specification isnot an admission that the publication, patent or patent application isprior art.

1. A catalyst composition comprising a ruthenium catalyst immobilized ona siliceous mesocellular foam support, wherein the ruthenium catalyst isselected from the group consisting of a Grubbs catalyst and aHoveyda-Grubbs catalyst.
 2. The catalyst composition according to claim1, wherein the ruthenium catalyst is the Grubbs catalyst.
 3. Thecatalyst composition according to claim 1, wherein the rutheniumcatalyst is the Hoveyda-Grubbs catalyst.
 4. A catalyst compositioncomprising a catalyst:

immobilized on a siliceous mesocellular foam support.
 5. The catalystcomposition according to claim 4, wherein the catalyst is immobilized onthe siliceous mesocellular foam support using a linking group comprisinga carbamate or silyl group.
 6. The catalyst composition according toclaim 5, wherein the carbamate or silyl group is attached to thesiliceous mesocellular foam support through an alkyl spacer.
 7. Thecatalyst composition according to claim 6, wherein the alkyl spacer is aC₁-C₆ alkyl group.
 8. The catalyst composition according to claim 5,wherein the carbamate is a methyl carbamate.
 9. The catalyst compositionaccording to claim 5, wherein the silyl group is substituted by one ortwo methyl groups.
 10. The catalyst composition according to claim 5,wherein the linking group is —X—C(O)N(H)CH₂CH₂CH₂—, and wherein X isCH₂O or O.
 11. The catalyst composition according to claim 5, whereinthe linking group is —Si(CH₃)₂—[(C₁-C₆)alkyl]_(n)-, and wherein n is 0,1, 2, 3, 4, 5, or
 6. 12. The catalyst composition according to claim 5,wherein the linking group is attached to the 2-position of the catalyst:


13. The catalyst composition according to claim 1, wherein the siliceousmesocellular foam support comprises trimethylsilyl.
 14. The catalystcomposition according to claim 1, wherein the siliceous mesocellularfoam support comprises spherical, monodisperse siliceous mesocellularfoam microparticles.
 15. The catalyst composition according to claim 14,wherein the siliceous mesocellular foam support comprises pores havingan average pore diameter of about 24 to about 42 nm.
 16. The catalystcomposition according to claim 1 for use in a ring-closing metathesisreaction.
 17. The catalyst composition according to claim 16, which isrecycled for use in a further ring-closing metathesis reaction.
 18. Amethod for preparing a catalyst composition comprising immobilizing aGrubbs catalyst or a Hoveyda-Grubbs catalyst on a siliceous mesocellularfoam support.
 19. The method according to claim 18, wherein the catalystis: